The mechanism by which cyclosporine (CsA) exerts its toxic effects on the kidney and other organ systems has been the subject of intensive ongoing research. However, there has been no thorough investigation of the effects of CsA on the male reproductive system. This is an important issue because an increasing number of young men are being treated with CsA on a long term basis either as organ transplant recipients or because they have an auto-immune disorder. In preliminary studies using a rat model we have shown that CsA has deleterious effects on the testis. CsA was taken up by both the tubular and intersititial compartments of the testis. In CsA treated rats testosterone levels declined, gonadotropin levels increased and the spermatogenic process was impaired. Consequently, sterility occurred. All the effects were dose dependent and were manifested within two weeks. The administration of testosterone propionate restored reproductive organ weights but not spermatogenesis, whereas withdrawal of the drug reversed the toxic effect of CsA completely. In addition, TP ameliorated the nephrotoxicity of CsA. The objective of this proposal is to evaluate the effects of CsA on testicular function - its mechanism prevention and clinical significance. We will examine, in particular the effect of CsA on the inhibition of steroidogenesis by testis. We will study the long term effects of low, therapeutic doses of CsA on spermatogenesis, Leydig cell and Sertoli cell functions, and fertility. We will try to reverse the harmful effects of CsA by hormonal therapy and withdrawal of drug treatment. We will also investigate the effects of androgen therapy on the nephrotoxic effects of CsA. Finally, we will conduct a clinical examination of CsA effects on hormone levels and semen parameters in human transplant patients.